The immune response of human beings can be re-energized to counter chronic viral infection, according to a study which has been published in the journal Nature. The research also provides a plan to improve T cell immunotherapy and therapeutic vaccines. The CD8 T cells of the immune system are subject to exhaustion while combating persistent viral infection, and become less effective over a period of time.
Researchers at Dana-Farber Cancer Institute and Emory University have traced the problem to a gene that turns off the infection-fighting drive of CD8 T cells in mice. The discovery raises the possibility that CD8 cell exhaustion can be reversed in human patients, reinvigorating the immune system's defenses against chronic viral infections ranging from hepatitis to HIV, the virus that causes AIDS.
"CD8 T cells that have fought viral infections retain a 'memory' of the viruses they've encountered, so they can rapidly respond to new infections from those viruses," said lead researcher Gordon Freeman.
In the case of chronic infection, however, senior author Rafi Ahmed has shown that memory cells become exhausted and lose the capacity to respond to the virus. To find the cause the researchers conducted a microarray experiment measuring the activity of thousands of genes in normal memory CD8 T cells in mice and in exhausted versions of those cells. They found that a gene known as PD-1 was much more active in the exhausted cells.
"When [co-author] John Wherry of the Wistar Institute found a high level of the PD-1 gene in microarray experiments, we wanted to test whether this was contributing to the CD8 exhaustion. We found that exhausted CD8 T cells in mice have unusually large numbers of PD-1 receptors, and blocking the PD-1/PD-L1 bond reactivated the cells' response to infection," said Freeman.
Just as strikingly, researchers found that even in persistently infected mice that lacked a type of T cell known as helper CD4, preventing PD-1 from binding to PD-L1 had a beneficial effect on "helpless" CD8 T cells -- restoring their ability to kill infected cells and release infection-fighting substances called cytokines, substantially reducing the animals' "viral load."